ABSTRACT Genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated SNPs are noncoding, and their functional implications remain unknown. We hypothesized that differential expression of the NRG1 gene explains its association to the disease. We examined four of the disease-associated SNPs that make up the original risk haplotype in the 5' upstream region of the gene for their effects on mRNA abundance of NRG1 types I-IV in human postmortem hippocampus. Diagnostic comparisons revealed a 34% increase in type I mRNA in schizophrenia and an interaction of diagnosis and genotype (SNP8NRG221132) on this transcript. Of potentially greater interest, a single SNP within the risk haplotype (SNP8NRG243177) and a 22-kb block of this core haplotype are associated with mRNA expression for the novel type IV isoform in patients and controls. Bioinformatic promoter analyses indicate that both SNPs lead to a gain/loss of putative binding sites for three transcription factors, serum response factor, myelin transcription factor-1, and High Mobility Group Box Protein-1. These data implicate variation in isoform expression as a molecular mechanism for the genetic association of NRG1 with schizophrenia.

mRNA expression than homozygous C?C individuals. However,standardposthoccontrastsbetweenthethreegroupsrevealedonlythe two homozygote groups to be significantly different in terms oftype IV abundance (post hoc t test; P ? 0.05; Fig. 3A). This effectappeared more pronounced in the schizophrenia group alone (Fig.3B), although no hint of a diagnosis ? genotype interaction wasobserved. Of note, normal control individuals homozygous for theT allele also showed the relatively greatest type IV NRG1 mRNAexpression (Fig. 3B).Significant diagnosis ? genotype interactions were found be-tween five of the six haplotype-tagging SNPs (htSNPs) and type IVmRNA abundance (rs4268090, rs4298458, rs4452759, rs4733263,and rs4476964) [range F (3, 100) ? 3.35–5.82; P ? 0.033–0.018]. Atrend for a main effect of genotype was observed for the htSNP,rs4268090 [F (3, 100) ? 3.55; P ? 0.06]. Carrying the T (2) alleleat this SNP was associated with higher levels of type IV mRNAcompared with subjects homozygous for the C (1?1) allele.Haplotype Analysis. Results of LD tests between pairs of all 10 5?SNPs in African American and Caucasian individuals can be foundinTables1and2,whicharepublishedassupportingmaterialonthePNAS web site. The four markers chosen from the deCODEhaplotypewereinsignificant,butmoderate,LDinbothgroups(seeSupporting Text). The frequencies for the four common haplotypescomprised of the four deCODE SNPs are shown in Table 3, whichispublishedassupportinginformationonthePNASwebsite).Hap4 contains the specific alleles that form part of the deCODEhaplotype.To test whether this four SNP risk haplotype (hap4) was asso-ciated with NRG1 mRNA levels, we used SNPHAP (www-gene.cimr.cam.ac.uk?clayton?software) to assign a diplotype (hap-lotype pair) to each individual. We then compared hap4 carriers(diplotypeshap1?hap4,hap2?hap4,hap3?hap4,andhap4?hap4)tonon-hap4 individuals (diplotypes hap1?hap1, hap1?hap2, hap1?hap3,hap2?hap2,hap3?hap3,andhap2?hap3),testingforaneffectof carrying the risk haplotype on NRG1 mRNA abundance.ANOVA revealed a main effect of hap4 on type IV mRNAabundance in the entire sample [F (3, 89) ? 3.38; P ? 0.04]. Hap4carriers had 27% more type IV mRNA compared with non-hap4individuals (Fig. 4A). This effect appeared more pronounced in theschizophrenic patients, where a 53% increase in type IV NRG1mRNA was seen in hap4 carriers compared to noncarriers; incontrols, only a 14% increase was observed (Fig. 4B). However, nodiagnosisbygenotypeinteractionwasfound.Racewasnotincludedas a factor in the analysis because of the small number of AfricanAmerican individuals carrying hap4. Hap4 showed no effect on theexpression of any of the other NRG1 isoforms.Promoter Analysis Based on Transcription Factor Binding Sites. As afurtherexplorationofthefunctionalrelevanceofdisease-associatedSNPs in the NRG1 gene, we performed an analysis of putativetranscription factor binding sites by using MATINSPECTOR software(Genomatix, Munich), a computational suite for promoter infor-matics. Two SNPs in the haplotype were indicated to be containedwithin transcriptional regulatory elements; notably, these elementswere the two SNPs that, as described above, were found to impactupon expression of NRG1 isoforms, SNP8NRG221132, which isassociated with type I NRG1, and SNP8NRG243177, which isassociated with type IV NRG1. SNP8NRG221132 is within apredicted transcription factor binding domain for serum responsefactor (SRF), with the risk allele (G) abolishing SRF binding.SNP8NRG243177isalsowithinaputativebindingsiteforSRFandfor myelin transcription factor 1. Carrying the risk allele (T) resultsin a predicted loss of binding to both of these transcription factorsFig. 3.243177 and type IV NRG1 mRNA expression.(A) In the whole cohort, a main effect ofgenotype was observed (ANOVA; P ? 0.04)An allele dose-dependent effect is sug-gested,withindividualshomozygousfortheriskallelehavingthehighestlevelsoftypeIVNRG1 mRNA (P ? 0.05). (B) Data parsed bydiagnosis. No genotype ? diagnosis interac-tion was observed.Association between SNP8NRG-Fig. 4.tainingthedeCODEriskhaplotype(hap4)andtype IV NRG1 mRNA. Individuals were dividedaccording to diplotype into two groups, non-hap4 carriers (haplotypes 1?1; 1?2, 1?3, 2?2,3?3, and 2?3) and hap4 carriers (haplotypes1?4, 2?4, 3?4, and 4?4). A main effect of dip-lotype was observed on normalized type IVNRG1 mRNA levels (ANOVA; P ? 0.04). (A)Individuals carrying the hap4 risk haplotypehad increased levels compared with individu-als not carrying hap4. (B) Effect of diplotypeon type IV NRG1 mRNA levels in controls andpatients.Elevenindividualswerenotincludedinthediplotypeanalysisbecauseofeitherthefailure of genotyping at one or more of theSNPs or low probability (?93%) of diplotypeassignment according to SNPHAP.Association between diplotypes con-Law et al.PNAS ?April 25, 2006 ?vol. 103 ?no. 17 ?6749NEUROSCIENCE

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and the acquisition of the transcription factor binding site for HighMobilityGroupBoxProtein-1.Noneoftheother8SNPsgenotypedin the study mapped to transcription factor binding domains.Analysis of Negative SNP Controls. The two negative control SNPs(rs10954867 and rs7005288) showed no association with anyNRG1 isoform in either controls or schizophrenic patients (allP ? 0.2).Regional Distribution of Hippocampal NRG1 mRNA in Schizophrenia.Because no information is available regarding the distribution ofNRG1 in the human hippocampus, and this data was not providedfrom the quantitative RT-PCR experiments, we examined NRG1mRNA in the hippocampus in schizophrenia by using in situhybridization with a ‘‘pan’’ NRG1 probe (Supporting Text; see alsoFig. 5, which is published as supporting information on the PNASwebsite).NodifferenceswereseeninthedistributionofpanNRG1mRNAbetweensubfieldsoritsoverallabundanceinschizophrenia.DiscussionWe have investigated the expression of NRG1 type I–IV mRNAin the human hippocampus and examined the effects of schizo-phrenia and disease-associated polymorphisms in the 5? up-stream region on expression of these transcripts. We hypothe-sized that the genetic association of NRG1 with schizophrenia ismediated by altered expression of the gene based on the locationand noncoding nature of the disease-associated polymorphismsand the fact that extensive sequencing of NRG1 has failed toidentify pathogenic coding mutations (6). We report threeprincipal findings: (i) up-regulation of type I expression in thehippocampus in schizophrenia, (ii) association of type I expres-sion with a single SNP residing in the original deCODE riskhaplotype, and (iii) association of type IV expression with asingle SNP and a four-marker haplotype representing the 5?upstream region of the original at-risk haplotype associated withschizophrenia. We provide evidence of association betweendisease linked-variation in NRG1 and altered NRG1 isoformexpression in the brain, and we propose that altered transcriptregulation is a potential molecular mechanism behind the ge-netic association of NRG1 with schizophrenia.Our finding of increased type I mRNA NRG1 expression in thehippocampus in schizophrenia replicates the finding in the dorso-lateral prefrontal cortex of a smaller and separate brain series (27).ThesefindingssuggestthatenhancedtypeIexpressionisrobustandfound in two separate brain regions in schizophrenia. In addition,we also replicate the finding that type II and type III isoformexpression is unaltered in schizophrenia, suggesting that theseisoforms may not be directly relevant to the pathophysiology of thedisease. However, we did observe increases in the relative abun-dance of type I to type II–IV, suggesting that the contribution oftheselatterisoformstoNRG1signalinginthehippocampusmaybeindirectly compromised in patients with schizophrenia. At present,it is unclear whether type I up-regulation in schizophrenia isprimary or secondary to other abnormalities in NRG1 isoformregulationortoothermolecularchangesassociatedwiththediseaseWhen the four individual SNPs representing the 5? region of thedeCODE at-risk haplotype were tested for association with type INRG1mRNA,nomaineffectsofgenotypewereseenforanyoftheSNPs. A diagnosis ? genotype interaction was observed at a singleSNP, SNP8NRG221132, and post hoc tests showed an effect ofgenotype only in control subjects on type I mRNA abundance. Ina second independent cohort of brains in which increased type ImRNA expression previously had been reported in the schizophre-niasamples,wefoundamaineffectofagenotypeatthisSNPintheentire sample and again a genotype by diagnosis interaction. Thismain effect of the genotype was not seen in the first cohort;however, we note that the main effect in the entire sample is drivenprimarily by the controls. The observations that the main effect ofthegenotypewasprimarilyinthecontrols,andthatthefour-markerrisk haplotype had no effect on type I NRG1 expression, raise thepossibility that SNP8NRG221132 influences type I expressionindependentofitscontributiontoriskforschizophrenia.Additionalsupport for the functional relevance of SNP8NRG221132 comesfrom the bioinformatic promoter analysis that predicts the riskallele (G) leads to a loss of binding for SRF. SRF is a transcriptionfactor that regulates the expression of genes encoding cytoskeletalproteins, such as cofilin and actin (32), both of which have beenlinked directly to NRG1s role in actin dynamics (33). The loss ofSRF binding in controls homozygous for the risk allele, therefore,may be related to lower levels of type I mRNA transcription, asreported here. The direct functional consequences of this SNP fortype I NRG1 transcriptional control remain difficult to predictbecause the SNP resides 1 Mb upstream from the transcriptionalstart site of type I. However, SNP8NRG221132 could conceivablyreside in a regulatory element of the gene, as is seen in other keydevelopmental genes where genomic regions harboring cis-regulatory elements can be located as far as 1 Mb from thetranscription unit (34).The interrelationship between SNP8NRG221132, type I NRG1expression, and schizophrenia is somewhat more difficult to inter-pret, because in contrast to the effect seen in controls, we did notsee a similar genotype effect in the patients. This issue is discussedin Supporting Text, Discussion: Genetic Association and Type IExpression in Schizophrenia).In contrast to the type I finding, which is not manifestly relatedto genetic variation in NRG1 associated with schizophrenia, theassociation between both SNP8NRG243177 and the four-markerat-risk haplotype with expression of a novel isoform of NRG1, typeIV, suggests that we may have identified a genetic mechanism andamolecularphenotypeunderlyingtheinvolvementofNRG1insus-ceptibility for schizophrenia. The risk allele of SNP8NRG243177and the deCODE haplotype predicted higher levels of type IVNRG1 expression in our entire sample. Analysis of the threegenotype groups for SNP8NRG243177 revealed that individualshomozygous for the risk allele had the highest levels of type IVexpression, with evidence of an allele dose-dependant effect. Thisobservation appeared more pronounced in the patients, althoughtrends in the same direction were found in the normal controlsand no diagnosis ? genotype interaction was observed.SNP8NRG243177 is the most 3? of the SNPs in the four-markerdeCODE haplotype and is located ?1.2 kb upstream of thetranscriptional start of type IV. Because none of the other singleSNPs in this haplotype were associated with type IV NRG1expression, our results suggest that SNP8NRG243177 is a func-tional polymorphic variant that regulates type IV NRG1 mRNAlevels or is in strong LD with a nearby functional mutation.Additionalsupport fortheSNP8NRG243177 for gene regulation comes from the bioinfor-matic prediction that this SNP determines a putative transcriptionfactor binding domain for SRF, myelin transcription factor 1, andHigh Mobility Group Box Protein-1. Of note, SRF and myelintranscription factor 1 play critical roles in neuronal migration,synaptic plasticity, and oligodendrocyte proliferation and survival,respectively, providing a striking molecular convergence with cur-rent hypotheses regarding the neurobiology of schizophrenia andthe potential role of NRG1 (35). However, we do not know which,if any, of these changes in transcription factor binding sites mightmediate the association between SNP8NRG243177 and type IVexpressionandschizophrenia.OfpotentialinterestisHighMobilityGroup Box Protein-1, an abundant chromatin-binding protein,whichactsasanarchitecturalfacilitatorintranscription(36).Inoursample, acquisition of two High Mobility Group Box Protein-1-binding motifs (i.e., homozygosity for the risk allele) was associatedwith significantly elevated type IV NRG1 expression, whereasacquisition of one (i.e., heterozygosity for the risk allele) was not.This observation suggests (i) that this binding site may potentiatefunctionalrelevanceof6750 ?www.pnas.org?cgi?doi?10.1073?pnas.0602002103 Law et al.

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type IV NRG1 transcription (and that SRF binding is necessary foroptimal levels of type IV transcription) and 2) that this effect maybe recessive.TheabsenceofoverallchangesintypeIVNRG1geneexpressionlevels in schizophrenia suggest that altered type IV, unlike type I,is not a general characteristic of the disease state, per se. Indeed, ifaltered NRG1 type IV expression is part of the genetic architectureofsusceptibilityforschizophrenia,itwouldnotbeexpectedtoshowan effect at the general population level, assuming that the at-riskhaplotype is relevant for, at most, 10% of cases. Furthermore, ourfinding that the deCODE risk haplotype is associated specificallywith type IV NRG1 expression argues that the clinical associationwith NRG1 is based on this molecular effect.We further report association of type IV NRG1 mRNA inschizophrenia with five additional htSNPs, which span a 17-kb gapbetween the four SNPs from the deCODE haplotype. To ourknowledge, these SNPs have not been tested for association withschizophrenia in the same clinical samples in which the deCODESNPs were positive. We genotyped these SNPs to address thepossibilitythatthedeCODEhaplotypemightnotprovidesufficientinformation regarding genetic diversity in our sample. None ofthese SNPs showed main effects, and their association with NRG1type IV expression in schizophrenia is likely via LD withSNP8NRG243177.In our sample, the deCODE risk haplotype, which we termedhap4, was present in both Caucasian and African American pop-ulationsbutmorecommonintheCaucasiansample.Thesignificantdegree of LD across this region of the gene suggests that, at leastin Caucasians, it has undergone very little recombination (37).Furthermore, the region is highly conserved between species,including chimpanzee, dog, mouse, and rat, suggesting that thisregionofthegeneisfunctional,probablyinvolvedintranscriptionalregulation of NRG1 (38). We found no evidence to suggest that thefrequency of the deCODE haplotype was higher in our patientpopulation compared with controls, but our sample is too small tomeaningfully test for association with clinical phenotype. Of note,we observed that the frequency of hap2 was somewhat greater inthe African American patients (34%) compared with AfricanAmerican controls (25%), suggesting that in different ethnicgroups, different haplotypes in the same region of the gene may beassociated with schizophrenia. However, because of the smallsample size involved, conclusions are limited. Interestingly, hap2 inthe African American sample contains the same allele atSNP8NRG243177 as hap4.In the original report by Stefansson et al. (6), association inIcelandic families was mapped to a seven-marker haplotype span-ning a 270-kb LD block starting at SNP8NRG221132 and endingwith a synonymous SNP in exon two (SNP8NRG433E1006) andtwo microsatellites in the second intron (478N14-848 and 420M9-13950). Evidence of association to this region of the gene in othersamples has been primarily to SNPs at the 5? end of this haplotype,encompassing the SNPs typed in this study. Thus, although wecannot exclude the possibility that the causative mutation(s) ac-countingforourassociationwithtypeIVliesdownstreamfromourtyped SNPs, we tend to doubt this possibility for three reasons: (i)the exon 2 SNP and the microsatellites typed in the deCODEhaplotype have not shown single point (pairwise) association withschizophrenia in any study (6, 18, 19, 39), in contrast to the fourSNPs tested here, (ii) the physical location of SNP8NRG243177(i.e., ?1,200 bases upstream from the exon 1 start site) makes it afarbettercandidateforbeinglocatedinatranscriptionalregulatoryregion for type IV, and (ii) this SNP is in a putative functionaltranscription factor binding domain.The known biological functions of NRG1 (9) fit well with currenthypotheses regarding the neurobiology of schizophrenia (35), in-cluding regulation of synaptogenesis, in vivo synaptic transmission,long-term potentiation, activity-dependent synaptic plasticity, andneuronal migration as well as neurotransmitter function (NMDA,GABA, ?-7, and dopamine) and oligodendrocyte biology, all ofwhich are proposed to interact or be altered in schizophrenia (30,40). Of particular relevance is the recent finding that NRG1down-regulates NMDA-receptor currents in prefrontal corticalpyramidal neurons and slices (41). These data suggest that in-creased expression of NRG1 type I or IV would translate intodecreasedNMDAreceptor-mediatedsignaling,oneoftheprincipalneurotransmitter hypotheses of schizophrenia.Finally, it should be noted that we have performed a number oftests in this study, and correction for multiple testing was notperformed. Correction for random effects, such as Bonferronicorrection, would be an excessively conservative approach, partic-ularlygiventhatwehaverestrictedourprimaryanalysestoplannedcomparisons(basedonstrongpriorclinicalassociationandphysicallocation of the SNPs) of four SNPs and a single haplotype com-prised of these SNPs. Because the SNPs are in moderate LD, thedegree of independence between markers is low and, therefore,correcting for multiple testing would result in a high type II errorrate. The prior probability and the predictable association betweenthe deCODE haplotype and expression of NRG1 isoforms (espe-cially type IV, which is its immediate physical neighbor) combinedwith the LD between SNPs in this haplotype makes statisticalcorrection for these comparisons inappropriate. Nevertheless, ourfinding regarding type IV expression and the deCODE haplotypeand SNP8NRG243177 requires independent replication.In summary, we provide evidence of splice variant-specificalterations of NRG1 gene expression in schizophrenia and dem-onstrate that disease-associated polymorphisms in a 5? regulatoryregion of NRG1 are associated with differential NRG1 isoformexpression. We suggest that the mechanism behind the clinicalassociation of NRG1 with schizophrenia is altered transcriptionalregulation, which modifies, probably to a small degree and in anisoform-limitedfashion,theefficiencyofNRG1signalingeffectsonneural development and plasticity. Such alterations may compro-misecorticalandhippocampalfunctionthroughoneormoreoftherolesofNRG1andreflect,atleastpartly,thecontributionofNRG1to the genetic risk architecture for the disease.Materials and MethodsHuman Postmortem Tissue. Postmortem hippocampal tissue wascollected at the Clinical Brain Disorders Branch, National Instituteof Mental Health, from 84 normal controls (22 females?62 males,53AfricanAmerican?25AmericanCaucasian?5Hispanic?1Asian,mean age 40.5 ? (SD) 15.4 years, PMI 30.7 ? 13.9 h, pH 6.59 ?0.32) and 44 schizophrenic patients (15 females?29 males, 24African Americans?20 Caucasians, mean age 49.7 ? 17.2 years,PMI 36.3 ? 17.7 h, pH 6.48 ? 0.28). This whole cohort was usedfor the analysis of effects of genetic variation on NRG1 isoformexpression. The different genotype groups in this cohort did notdiffer on any of the potential variables that affect gene expressionin the human postmortem brain (i.e., age, PMI, pH, and age).Because the diagnostic groups in the whole cohort were notperfectly matched for these variables, we selected a subcohort of 53controls (17 females?36 males, 31 African Americans?17 Cauca-sians?5Hispanicindividuals,meanage44?14.2years,PMI33.3?13.7, pH 6.53 ? 0.24) and 38 schizophrenic individuals (12 fe-males?26 males, 18 African Americans?19 Caucasians?1 Hispanicindividuals,meanage49.3?19.3years,PMI38.1?18.8,pH6.40?0.26), matched for these potential confounding variables. ThissubcohortwasusedfordiagnosticcomparisonsofNRG1expressionlevels. Details of brain collection, neuroleptic medication history,and RNA extraction are described in Supporting Text.Oligonucleotide and Primer Design. Primer and probe designs forNRG1 types I–III were as described in ref. 27. Details of type IVandtypeI–IIIdesigncanbefoundinSupportingText(seealsoTable4,whichispublishedassupportinginformationonPNASwebsite).Law et al.PNAS ?April 25, 2006 ?vol. 103 ?no. 17 ?6751NEUROSCIENCE

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[Show abstract][Hide abstract]ABSTRACT:
The neuropathological basis of schizophrenia and related psychoses remains elusive despite intensive scientific investigation. Symptoms of psychosis have been reported in a number of conditions where normal myelin development is interrupted. The nature, location, and timing of white matter pathology seem to be key factors in the development of psychosis, especially during the critical adolescent period of association area myelination. Numerous lines of evidence implicate myelin and oligodendrocyte function as critical processes that could affect neuronal connectivity, which has been implicated as a central abnormality in schizophrenia. Phenocopies of schizophrenia with a known pathological basis involving demyelination or dysmyelination may offer insights into the biology of schizophrenia itself. This article reviews the pathological changes in white matter of patients with schizophrenia, as well as demyelinating diseases associated with psychosis. In an attempt to understand the potential role of dysmyelination in schizophrenia, we outline the evidence from a number of both clinically-based and post-mortem studies that provide evidence that OMR genes are genetically associated with increased risk for schizophrenia. To further understand the implication of white matter dysfunction and dysmyelination in schizophrenia, we examine diffusion tensor imaging (DTI), which has shown volumetric and microstructural white matter differences in patients with schizophrenia. While classical clinical–neuropathological correlations have established that disruption in myelination can produce a high fidelity phenocopy of psychosis similar to schizophrenia, the role of dysmyelination in schizophrenia remains controversial.

[Show abstract][Hide abstract]ABSTRACT:
Background: Substantial evidence from human postmortem and genetic studies have linked the neurotrophic factor neuregulin 1 (NRG1) to the pathophysiology of schizophrenia. Genetic animal models and in vitro experiments have suggested that altered NRG1 signaling, rather than protein changes, contributes to the symptomatology of schizophrenia. However, little is known about the effect of NRG1 on schizophrenia-relevant behavior and neurotransmission (particularly GABAergic and glutamatergic) in adult animals.
METHOD:
To address this question, we treated adult mice with the extracellular signaling domain of NRG1 and assessed spontaneous locomotor activity and acoustic startle response, as well as extracellular GABA, glutamate and glycine levels in the prefrontal cortex and hippocampus via microdialysis. Furthermore, we asked whether the effect of NRG1 would differ under schizophrenia-relevant impairments in mice and therefore co-treated mice with NRG1 and phencyclidine (3 mg/kg).
RESULTS:
Acute intraventricularly or systemically injected NRG1 did not affect spontaneous behavior, but prevented PCP-induced hyperlocomotion and deficits of prepulse inhibition. Following on, NRG1 retrodialysis (10 nM) reduced extracellular glutamate and glycine levels in the prefrontal cortex and hippocampus, and prevented PCP-induced increase in extracellular GABA levels in the hippocampus.
CONCLUSION:
With these results we provide the first compelling in vivo evidence for the involvement of NRG1 signaling in schizophrenia-relevant behavior and neurotransmission in the adult nervous system and highlight its treatment potential. Furthermore, the ability of NRG1 treatment to alter GABA, glutamate and glycine levels in the presence of PCP also suggests that NRG1 signaling has the potential to alter disrupted neurotransmission in patients with schizophrenia.

[Show abstract][Hide abstract]ABSTRACT:
The GRIA1 locus, encoding the GluA1 (also known as GluRA or GluR1) AMPA glutamate receptor subunit, shows genome-wide association to schizophrenia. As well as extending the evidence that glutamatergic abnormalities have a key role in the disorder, this finding draws attention to the behavioural phenotype of Gria1 knockout mice. These mice show deficits in short-term habituation. Importantly, under some conditions the attention being paid to a recently presented neutral stimulus can actually increase rather than decrease (sensitization). We propose that this mouse phenotype represents a cause of aberrant salience and, in turn, that aberrant salience (and the resulting positive symptoms) in schizophrenia may arise, at least in part, from a glutamatergic genetic predisposition and a deficit in short-term habituation. This proposal links an established risk gene with a psychological process central to psychosis and is supported by findings of comparable deficits in short-term habituation in mice lacking the NMDAR receptor subunit Grin2a (which also shows association to schizophrenia). As aberrant salience is primarily a dopaminergic phenomenon, the model supports the view that the dopaminergic abnormalities can be downstream of a glutamatergic aetiology. Finally, we suggest that, as illustrated here, the real value of genetically modified mice is not as 'models of schizophrenia' but as experimental tools that can link genomic discoveries with psychological processes and help elucidate the underlying neural mechanisms.Molecular Psychiatry advance online publication, 16 September 2014; doi:10.1038/mp.2014.91.